心阳片抑制MLK3/JNK/P53介导的心肌细胞铁死亡抗慢性心力衰竭的作用及机制研究  

Effects and mechanism of Xinyang Tablet on inhibiting cardiomyocyte cell ferroptosis mediated by MLK3/JNK/p53 and preventing chronic heart failure

作　　者：王俊岩 黄育生[1] 刘青[1] 周政[1] 邓波[1] 汪朝晖[1] 王陵军[1] 冼绍祥[1] WANG Jim-yan;HUANG Yu-sheng;LIU Qing;ZHOU Zheng;DENG Bo;WANG Zhao-hui;WANG Ling-jun;XIAN Shao-xiang(Guangzhou University of Chinese Medicine,Guangzhou 510405,China)

机构地区：[1]广州中医药大学,广州510405

出　　处：《中华中医药杂志》2020年第5期2604-2607,共4页China Journal of Traditional Chinese Medicine and Pharmacy

基　　金：国家自然科学基金项目(No.81673920,No.81673796,No.81804048,No.81973776,No.81973777);广东省自然科学基金项目(No.2017A030313454,No.2016A030311030);广州中医药大学第一临床医学院优秀博士学位论文培育项目(No.YB201904)

摘　　要：目的:探讨MLK3/JNK/p53介导的心肌细胞铁死亡在慢性心力衰竭(CHF)中的作用机制及心阳片的干预作用。方法:随机将80只C57BL/6J小鼠分为假手术组,模型组,URMC-099+假手术组,URMC-099组,心阳片低、中、高剂量组,培哚普利组,采用胸主动脉缩窄(TAC)术复制压力负荷CHF模型。心阳片低、中、高剂量组分别给予心阳片0.34、0.68、1.36g/kg灌胃,培哚普利组给予培哚普利0.607mg/kg灌胃,URMC-099组给予URMC-099 10mg/kg,2次/d,于造模1周前开始腹腔注射,假手术组和模型组给予等量0.9%氯化钠溶液灌胃。连续给药8周后,小动物超声检测各组小鼠心功能,HE染色检测各组小鼠心脏组织形态学变化,Masson染色检测各组小鼠心脏胶原纤维沉积情况,Western Blot检测心脏组织MLK3、JNK、p53、COX2、xCT、GPX4、FTH1蛋白表达情况。结果:与假手术组比较,模型组小鼠LVEF和LVFS值显著降低(P<0.01),心脏细胞形态明显增大,排列不规则,有较多炎性细胞聚集及胶原纤维沉积,MLK3、JNK、p53、COX2蛋白水平显著升高(P<0.01),xCT、GPX4、FTH1水平显著降低(P<0.01);与模型组比较,各治疗组治疗后各项指标均得到显著改善(P<0.01)。结论:心阳片能抑制心肌纤维化来有效改善CHF小鼠心功能,其机制可能是通过抑制MLK3/JNK/p53介导的心肌细胞铁死亡发挥作用。Objective: To explore the mechanism of cardiomyocyte cell ferroptosis mediated by MLK3/JNK/p53 in chronic heart failure(CHF) and the effects of Xinyang Tablet. Methods: Eighty C57 BL/6 J mice were randomly divided into sham operated group, model group, URMC-099+sham operation group, URMC-099 group, Xinyang Tablet low, medium and high dose group, and Perindopril group. The CHF model induced by pressure loading was reproduced by thoracic aortic coarctation(TAC). Xinyang Tablet was given 0.34, 0.68, 1.36 g/kg by gavage in Xinyang Tablet low, medium and high dose group, respectively. Perindopril group was given 0.607 mg/kg perindopril by gavage. Mice in URMC-099 group were intraperitoneally injected with URMC-099 10 mg/kg twice a day within one week before modeling. The sham operation group and the model group were given the same amount of normal saline. After 8 weeks of continuous administration, the cardiac function of mice in each group was detected by ultrasound, the morphological changes of the hearts of mice in each group were detected by HE staining, the deposition of collagen fibers in the hearts of mice in each group was detected by Masson staining, and the expression of MLK3, JNK, p53, COX2, xCT, GPX4 and FTH1 proteins in the hearts of mice in each group was detected by Western Blot. Results: Compared with the sham operation group, in the model group, the LVEF and LVFS values were significantly reduced(P<0.01), the morphology of the heart cells was significantly enlarged and the arrangement was irregular, and there were more inflammatory cell aggregation and collagen fiber deposition, in addition, the levels of MLK3, JNK, p53 and COX2 increased significantly(P<0.01), while the levels of xCT, GPX4 and FTH1 decreased significantly(P<0.01). Compared with the model group, the indexes of each treatment group were significantly improved(P<0.01). Conclusion: Xinyang Tablet can effectively improve the cardiac function of mice with CHF by inhibiting myocardial fibrosis, and its mechanism may be achieved by inhibitin

关 键 词：心阳片 慢性心力衰竭 铁死亡 氧化应激 MLK3/JNK/P53信号通路 机制 心肌细胞 

分 类 号：R285.5[医药卫生—中药学]